Diabetes mellitus is a major cause of cardiovascular morbidity and mortality in the United States. Enhanced platelet function participates in the pathogenesis of vascular complications. We have recently observed that there is significant thromboxane release from diabetic platelets particularly during hyperglycemia and that aldose reductase may play a significant role in promoting platelet hyperactivity. Our goals are to discover the mechanism by which hyperglycemia is transduced into thromboxane release contributing to diabetic platelet dysfunction. Through three Specific Aims we will initially addres the role of aldose reductase in transducing this high glucose signal to platelet dysfunction (Specific Aim #1). Specific Aim #2 will determine whether this signaling process may contribute to aspirin insensitivity that is often observed among diabetic patients, and Specific Aim #3 will assess how newly discovered genetic variants may influence both the response to hyperglycemia and aspirin insensitivity. At the conclusion of this research program we will have identified and confirmed a key metabolic and signaling component that transduces acute and chronic hyperglycemia into enhanced platelet activity. The results of these studies may support proceeding with clinical trials to determine what combination of antiplatelet agents would be most beneficial to protect against cardiovascular disease in diabetic patients.